Steroidal hormone intermediates



Patented Apr. 1, 1947 STEROIDAL HORMONE INTERMEDIATES Russell EarlMarker, Mexico City, Mexico, as-

signor to Parke, Davis & Company, Detroit, Mich., a corporation ofMichigan No Drawing.

Original application February 5,

1940, Serial No. 317,419. Divided and this application May 24, 1944,Serial No. 537,192

4 Claims. (Cl. 260397.3)

This invention relates to steroidal hormone intermediates andpreparation of the same, and, more particularly, to the preparation ofnew steroidal sapogenin derivatives useful as intermediates for themanufacture of hormones.

This application is a division of my copending application, Serial No.317,419, filed February 5, 1940.

Qne of the objects of this invention is to prepare new steroidalsapogenin derivatives which can readily be converted to pregnanederivatives.

In my copending application, Serial No. 393,667, filed May 15, 1941, Ihave set forth the preparation of new sapogenin derivatives which Idesignate as pseudo-sapogenins and have also set forth the manner inwhich the pseudosapogenins may be oxidized to form A -20-ketopregnenecompounds, i. e. steroids having in ring D the structure In my copendingapplication, Serial No. 393,668, filed May 15, 1941 (now Patent No.2,291,643, issued August 4, 1942) I have disclosed and claimed a certaingroup of A -20-keto-pregnene compounds which are easily prepared fromthe readily available sarsasapogenin.

In the parent application, Serial No. 317,419 I have disclosed andclaimed another valuable group of A -20-keto-pregnene compounds havingat C3 and at one of C2 and C6, a member of the class consisting of -OHand groups hydrolyzable to -OH.

The compounds of the instant divisional application areZO-Keto-pregnenes having at C3, Cs

and C20, ketc groups or groups capable of hydrolysis to keto groups.

The compounds of this invention may be obtained, for example, from theknown sapogenins, chlorogenin, diosgenin and gitogenin which differ fromone another only in regard to the connections between rings A and B, thedegree of saturation of the ring system and the number of substituentsattached to these rings.

The structures of rings A and B of these compounds are shown below:

HO I

Chlorogenin Diosgenin Gitogenin The invention is illustrated by thefollowing examples.

Example I (a) A mixture of 2.5 grams of chlorogenin and 30 cc. of aceticanhydride is heated at 200 for 10 hours. The acetic anhydride is thenevaporated in vacuo and the sirupy residue hydrolyzed with hot alcoholicpotassium hydroxide. The small white crystals which separate on dilutionare collected and washed well with alcohol. The product thus obtained ispseudo-chlorogenin and after recrystallization from acetone has the M.P. 268-270 C. It gives a large depression with a sample of chlorogenin.The substance is very sparingly soluble in acetone, ethyl acetate,ether, alcohol and similar solvents.

(b) 2 grams of pseudo-chlorogenin as thus prepared are dissolved in 300cc. of acetic acid and a solution of 2 grams of chromic anhydride in 20cc. of acetic acid is added at room temperature. After standing forabout an hour,

' a small amount of alcohol is added and most of the acetic acid removedby vacuum distillation. The residue is dissolved in ether and washedwell with water and dilute sodium hydroxide solution. The etherealextract is evaporated to dryness on a steam bath and the residuerecrystallized from alcohol. Thus there is obtained crystals of A-allo-pregnenetrione-3,6,20, M. P. 226 C.

(c) Five-tenths of a gram of A -pregnenetrione-3,6,20 is dissolved incc. of acetic acid and shaken in the presence of 0.5 gram of Adamsplatinum oxide catalyst in a hydrogen atmosphere at about 40 lbs.pressure for 3 hours. Then the catalyst is removed by filtrationand theacetic acid evaporated in vacuo. The residue may be crystallized fromacetone to give allopregnanetriol-3.6.20 as white crystals. On oxidationwith an equal weight of chromic anhydride in acetic acid solution atroom temperature and (a) A mixture of 2 grams of diosgenin, 30 cc. ofbenzoyl chloride and 15 grams of freshly fused sodium acetate is heatedin an oil bath at 220 C.

for hours. Then the mixture is distilled in vacuo until no moredistillate can be collectedat 200 C. and 10 mm. pressure. The residue inthe distilling flask is cooled and alcoholic sodium hydroxide solutionis added. After warming for one-half hour, the mixture is diluted withwater and ether, and the layers separated. The ethereal layer is washedwith water and dilute sodium hydroxide and then evaporated to dryness ona steam bath. This residue is pseudo-diosgenin. It may be purified bycrystallization from slightly diluted alcohol and is thus obtained aswhite crystals which readily decolorize bromine in acetic acid.

(b) One gram of pseudo-diosgenin is dissolved in 100 cc. of acetic acid.Five cc. of sulfuric acid are added and then in small portions, and withconstant stirring, there is added 1 gram of powdered potassiumpermanganate. After stirring for 6 hours at room temperature, sulfurdioxide is passed into the mixture with cooling until the solution isnearly colorless. The mixture is concentrated in vacuo to a small volumeand then diluted with water and ether extracted. The ethereal layer iswashed well with dilute alkali and water, and evaporated to dryness.The. yellow residue may be recrystallized from acetone to give yellowcrystals of M i-pregnadiene-trione-3,6,20.

(c) To 200 mgs. of theabove A -pregnadienetrione -3,6,20 in 10. cc. ofacetic acid is added 500 mgs. of zinc. dust and. the mixture heated for-1 hour on the steam bath. The mixture is diluted with water andextracted with ether and the ethereal extract washed well with water anddilute alkali. The ether is removed on the steam bath and the residuecrystallized from slightly diluted methanol. This product isallo-pregnanetrione-3,6,20

The new compounds of this invention may be represented generally by thefollowing formula REFERENCES CITEI') The following references are ofrecord in the file of this patent:

Reichstein, Helv. Chim, Acta," vol. 21, pages 161-71 (1938).

